WO2023016477A1 - Inhibiteur de kinases cycline-dépendantes - Google Patents

Inhibiteur de kinases cycline-dépendantes Download PDF

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Publication number
WO2023016477A1
WO2023016477A1 PCT/CN2022/111324 CN2022111324W WO2023016477A1 WO 2023016477 A1 WO2023016477 A1 WO 2023016477A1 CN 2022111324 W CN2022111324 W CN 2022111324W WO 2023016477 A1 WO2023016477 A1 WO 2023016477A1
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optionally substituted
compound
ring
membered
group
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PCT/CN2022/111324
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English (en)
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WO2023016477A9 (fr
Inventor
Dawei Wan
Lei MO
Kai Li
Junkai Huang
Yongping Xie
Li Zhou
Xiaohui Hu
Xiaoming ZOU
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Taizhou Eoc Pharma Co., Ltd.
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Application filed by Taizhou Eoc Pharma Co., Ltd. filed Critical Taizhou Eoc Pharma Co., Ltd.
Priority to US18/682,476 priority Critical patent/US20240352016A1/en
Priority to CN202280055252.7A priority patent/CN117916235A/zh
Priority to JP2024508806A priority patent/JP2024534028A/ja
Priority to EP22855458.0A priority patent/EP4380930A4/fr
Publication of WO2023016477A1 publication Critical patent/WO2023016477A1/fr
Publication of WO2023016477A9 publication Critical patent/WO2023016477A9/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • CDK Cyclin-dependent kinase
  • ring A is optionally substituted 5-ring-membered heteroaryl containing one or more N (nitrogen) .
  • said R 1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.
  • R 1 is H (hydrogen) , F (fluorine) or Cl (chlorine) .
  • said R 6 is selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted (C 1 -C 6 ) alkyl, and 3 to 12-ring-membered carbocycle.
  • said R 6 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R 6 is optionally substituted ethyl or optionally substituted propyl.
  • said R 6 is optionally substituted isopropyl.
  • said R 6 is optionally substituted 3 to 12-ring-membered carbocycle.
  • said R 6 is optionally substituted 5-ring-membered carbocycle.
  • said R 6 is optionally substituted cyclopentanyl.
  • said R 7 is selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted (C 1 -C 6 ) acyl, optionally substituted (C 1 -C 6 ) alkyl, optionally substituted 3 to 12-ring-membered carbocycle, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7 is optionally substituted (C 1 -C 6 ) acyl.
  • said R 7 is optionally substituted formyl.
  • said R 7 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R 7 is optionally substituted methyl or optionally substituted propyl.
  • said R 7 is optionally substituted 3 to 12-ring-membered carbocycle.
  • said R 7 is optionally substituted cyclohexyl.
  • said R 7 is optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7 is optionally substituted 6-ring-membered heterocycle.
  • said R 7 is optionally substituted piperidinyl.
  • said R 7 is optionally substituted 1-azabicyclo [2.2.2] octane.
  • said R 7-1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted 3 to 12-ring-membered carbocycle, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7-1 is optionally substituted hydroxy.
  • said R 7-1 is optionally substituted amino.
  • said R 7-1 is optionally substituted 3 to 12-ring-membered carbocycle.
  • said R 7-1 is optionally substituted cyclohexyl.
  • said R 7-1 is optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7-1 is optionally substituted 6-ring-membered heterocycle.
  • said R 7-1 is optionally substituted piperidinyl.
  • said R 7-2 is selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, and optionally substituted amino.
  • said ring B is optionally substituted 3 to 12-ring-membered heterocycle.
  • said ring B is optionally substituted 5 to 6-ring-membered heterocycle.
  • said ring B is optionally substituted 5 to 6-ring-membered heterocycle containing one or two N.
  • said ring B is optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted tetrahydropyrrolyl.
  • said R B-1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted (C 1 -C 6 ) acyl, optionally substituted (C 1 -C 6 ) alkyl, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R B-1 is optionally substituted (C 1 -C 6 ) acyl.
  • said R B-1 is optionally substituted formyl.
  • said R B-1 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R B-1 is optionally substituted methyl.
  • said R B-1 is optionally substituted 3 to 12-ring-membered heterocycle.
  • said R B-1 is optionally substituted 6-ring-membered heterocycle.
  • said R B-1 is optionally substituted piperidinyl.
  • said R B-2 is selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted (C 1 -C 6 ) alkyl, and optionally substituted 5 to 12-ring-membered heteroaryl.
  • said R B-2 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R B-2 is optionally substituted methyl, or optionally substituted ethyl.
  • said R B-2 is optionally substituted 5-ring-membered heteroaryl.
  • said R B-2 is optionally substituted 5-ring-membered heteroaryl containing two N.
  • said R B-2 is optionally substituted pyrazolyl.
  • said R B-3 is selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted (C 1 -C 6 ) alkyl.
  • said R B-3 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R B-3 is optionally substituted methyl.
  • said R B-4 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.
  • said ring A is optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A is optionally substituted pyrazolyl.
  • said R A-1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted (C 1 -C 6 ) acyl, optionally substituted (C 1 -C 6 ) alkyl, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R A-1 is optionally substituted (C 1 -C 6 ) acyl.
  • said R A-1 is optionally substituted formyl.
  • said R A-1 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R A-1 is optionally substituted methyl, or optionally substituted propyl.
  • said R A-1 is optionally substituted isopropyl.
  • said R A-1 is optionally substituted 6-ring-membered heterocycle.
  • said R A-1 is optionally substituted 6-ring-membered heterocycle containing two N.
  • said R A-1 is optionally substituted piperazinyl.
  • said R A-2 is selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted (C 1 -C 6 ) alkyl, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R A-2 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R A-2 is optionally substituted propyl.
  • said R A-2 is optionally substituted isopropyl.
  • said R A-2 is optionally substituted 6-ring-membered heterocycle.
  • said R A-1 is optionally substituted 6-ring-membered heterocycle containing two N.
  • said R A-2 is optionally substituted piperazinyl.
  • said R A-3 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • said R A-3 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R A-3 is optionally substituted methyl or optionally substituted ethyl.
  • said R A-4 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.
  • the present disclosure provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound is selected from the group consisting of:
  • ring A is 5-ring-membered heteroaryl containing one or more N (nitrogen) , said ring A is substituted with R A-1 , said R A-1 is optionally substituted alkyl, said ring A is further optionally substituted with optional substituents.
  • R 1 is H (hydrogen) , or Cl (chlorine) .
  • said R 6 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R 6 is optionally substituted propyl.
  • said R 6 is optionally substituted isopropyl.
  • said R 7 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7 is optionally substituted 6-ring-membered heterocycle.
  • said R 7 is optionally substituted piperidinyl.
  • said ring B is optionally substituted 6-ring-membered heterocycle.
  • said ring B is optionally substituted piperidinyl.
  • said ring B is substituted with one or more R B-1 , each said R B-1 is independently optional substituent.
  • said R B-1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, and optionally substituted amino.
  • said ring A is optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A is optionally substituted pyrazolyl.
  • said R A-1 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R A-1 is optionally substituted methyl, or optionally substituted propyl.
  • said R A-1 is optionally substituted isopropyl.
  • said R A-1 is substituted with one or more R A-2 , each said R A-2 is independently optional substituent.
  • said R A-2 is optionally substituted 6-ring-membered heterocycle.
  • said R A-2 is optionally substituted 6-ring-membered heterocycle containing two N.
  • said R A-2 is optionally substituted piperazinyl.
  • said R A-2 is substituted with one or more R A-3 , each said R A-3 is independently optional substituent.
  • said R A-3 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • said R A-3 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R A-3 is optionally substituted methyl or optionally substituted ethyl.
  • said R A-3 is substituted with one or more R A-4 , each said R A-4 is independently optional substituent.
  • said R A-4 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.
  • the present disclosure provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound is selected from the group consisting of:
  • ring A is 5-ring-membered heteroaryl containing one or more N (nitrogen) , said ring A is substituted with R A-1 , said R A-1 is optionally substituted ring, said ring A is further optionally substituted with optional substituents.
  • said R 1 is H (hydrogen) .
  • said R 6 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R 6 is optionally substituted propyl.
  • said R 6 is optionally substituted isopropyl.
  • said ring B is optionally substituted 6-ring-membered heterocycle.
  • said ring B is optionally substituted piperidinyl.
  • said ring B is substituted with one or more R B-1 , each said R B-1 is optional substituent.
  • said R B-1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted amino.
  • said ring A is optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A is optionally substituted pyrazolyl.
  • said R A-1 is optionally substituted 3 to 12-ring-membered heterocycle.
  • said R A-1 is optionally substituted 6-ring-membered heterocycle.
  • said R A-1 is optionally substituted 6-ring-membered heterocycle containing two N.
  • said R A-1 is optionally substituted piperazinyl.
  • said R A-1 is substituted with one or more R A-2 , each said R A-2 is independently optional substituent.
  • said R A-2 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R A-2 is optionally substituted propyl.
  • said R A-2 is optionally substituted isopropyl.
  • the present disclosure provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound is:
  • ring A is 5-ring-membered heteroaryl containing one or more N (nitrogen)
  • said ring B is 5 to 6-ring-membered heterocycle.
  • said R 1 is H (hydrogen) .
  • said R 6 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R 6 is optionally substituted propyl.
  • said R 6 is optionally substituted isopropyl.
  • said ring B is optionally substituted piperidinyl or optionally substituted tetrahydropyrrolyl.
  • R B-2 is H.
  • n 2
  • said ring A is optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A is optionally substituted pyrazolyl.
  • the present disclosure provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound is:
  • ring A is 5-ring-membered heteroaryl containing one or more N (nitrogen) ,
  • R B-2 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R 1 is H (hydrogen) .
  • said R 6 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R 6 is optionally substituted propyl.
  • said R 6 is optionally substituted isopropyl.
  • said ring B is optionally substituted piperidinyl.
  • said R B-2 is optionally substituted methyl.
  • said ring A is optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A is optionally substituted pyrazolyl.
  • the present disclosure provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound is:
  • ring A is 5-ring-membered heteroaryl containing one or more N (nitrogen)
  • one of said R B-2 is optionally substituted (C 2 -C 6 ) alkyl.
  • R 1 is H (hydrogen) .
  • said R 6 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R 6 is optionally substituted propyl.
  • said R 6 is optionally substituted isopropyl.
  • said ring B is optionally substituted piperidinyl.
  • said R B-2 is optionally substituted ethyl.
  • n 2
  • said ring A is optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A is optionally substituted pyrazolyl.
  • the present disclosure provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound is:
  • the present disclosure provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound is selected from the group consisting of:
  • the present disclosure provides a compound having the structure of formula (II) ,
  • each R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is independently absent or is independently selected from optional substituents, or R 6 and R 7 combined with the atoms to which they are attached form an optionally substituted ring,
  • ring A is optionally substituted ring.
  • said R 1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.
  • said R 1 is H (hydrogen) .
  • said R 5 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • said R 5 is optionally substituted (C 1 -C 6 ) alkyl.
  • said R 5 is optionally substituted propyl.
  • said R 5 is optionally substituted isopropyl.
  • said R 6 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 6 is optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 6 is optionally substituted 6-ring-membered heterocycle.
  • said R 6 is optionally substituted piperidinyl.
  • said ring B is optionally substituted 6-ring-membered heterocycle.
  • said ring B is optionally substituted piperidinyl.
  • said R B-1 is selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted amino.
  • said ring A is optionally substituted 5 to 12-ring-membered heteroaryl.
  • said ring A is optionally substituted 5-ring-membered heteroaryl.
  • said ring A is optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A is optionally substituted pyrazolyl.
  • the present disclosure provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound is selected from the group consisting of:
  • the present disclosure provides a composition
  • a composition comprising a compound of present disclosure, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, and optionally a pharmaceutically acceptable carrier.
  • the present disclosure provides a method for inhibiting cyclin-dependent kinase (CDK) activity, said method comprising administering to a subject in need thereof an effective amount of the compound of present disclosure, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing.
  • CDK cyclin-dependent kinase
  • CDK cyclin-dependent kinase
  • said method is selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.
  • alkyl generally refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to twenty carbon atoms; for example, from one to twelve carbon atoms; in another example, from one to ten carbon atoms; in another embodiment, from one to six carbon atoms; and in another embodiment, from one to four carbon atoms (such as 1, 2, 3 or more carbon atoms) .
  • a linear or branched-chain saturated hydrocarbyl substituent i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen
  • substituents may include e.g., methyl, ethyl, propyl (including n-propyl and isopropyl) , butyl (including n-butyl, isobutyl, sec-butyl and terf-butyl) , pentyl, isoamyl, hexyl and the like.
  • the number of carbon atoms in a hydrocarbyl substituent i.e., alkyl, alkenyl, cycloalkyl, aryl, etc.
  • C 1 -C 6 alkyl may refer to an alkyl substituent containing from 1 to 6 carbon atoms.
  • the “alkyl” groups may be optionally substituted with one or more substitutions.
  • alkenyl generally refers to a linear or branched-carbon radicals having at least one carbon-carbon double bond.
  • the term “alkenyl” may contain conjugated and non-conjugated carbon-carbon double bonds or combinations thereof.
  • An alkenyl group for example and without being limited thereto, may contain two to about twenty carbon atoms or, in a particular embodiment, two to about twelve carbon atoms. In embodiments, alkenyl groups may contain two to about four carbon atoms (such as 2, 3 or more carbon atoms) .
  • alkenyl groups include, but are not limited thereto, ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl contain groups having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. In some instances, the number of carbon atoms may be indicated by the prefix “C a -C b ” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent.
  • the “alkenyl” groups may be optionally substituted with one or more substitutions.
  • alkynyl generally refers to linear or branched carbon radicals having at least one carbon-carbon triple bond.
  • the term “alkynyl” may contain conjugated and non-conjugated carbon-carbon triple bonds or combinations thereof.
  • Alkynyl group for example and without being limited thereto, may contain two to about twenty carbon atoms or, in a particular embodiment, two to about twelve carbon atoms. In embodiments, alkynyl groups may contain two to about ten carbon atoms. Some examples may be alkynyl having two to about four carbon atoms (such as 2, 3 or more carbon atoms) .
  • the number of carbon atoms may be indicated by the prefix “C a -C b ” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent.
  • Examples of such groups include propargyl, butynyl, and the like.
  • the “alkynyl” groups may be optionally substituted with one or more substitutions.
  • amino As used herein, the term “amino” , either alone or within other terms, generally refers to formula -NH 2 group.
  • the “amino” groups may be optionally substituted with one or more substitutions.
  • ring generally refers to a ring system or a ring structure.
  • ring may comprise carbocycle, heterocycle, aryl, or heteroaryl.
  • ring membered or “membered ring” generally refers to a ring system having ring atoms.
  • n ring membered or “n-membered ring” generally refers to a ring system having n ring atoms.
  • 5 ring membered or “5-membered ring” generally refers to a ring system having 5 ring atoms which optionally contains one or more further heteroatom (s) selected from O, S or N.
  • the term “carbocycle” generally refers to a saturated or unsaturated non-aromatic monocyclic, bicyclic, or polycyclic ring system having from 3 to 14 ring atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein) wherein all of the ring atoms are carbon atoms.
  • Monocyclic carbocycles may have 3 to 6 ring atoms, or 5 to 6 ring atoms.
  • Bicyclic carbocycles may have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4, 5] , [5, 5] , [5, 6] or [6, 6] system, or 9 or 10 ring atoms arranged as a bicyclo [5, 6] or [6, 6] system.
  • the term “carbocycle” may contain, for example, a monocyclic carbocycle ring fused to an aryl ring (e.g., a monocyclic carbocycle ring fused to a benzene ring) .
  • Carbocyles may have 3 to 8 carbon ring atoms.
  • the number of carbon atoms may be indicated by the prefix “C a -C b ” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent.
  • the “carbocycle” groups may be optionally substituted with one or more substitutions.
  • heterocycle generally refers to a monocyclic, bicyclic, or polycyclic ring system having from 3 to 14 ring atoms (also referred to as ring members) wherein at least one ring atom in at least one ring may be a heteroatom selected from N, O, P, or S (and all combinations and subcombinations of ranges and specific numbers of carbon atoms and heteroatoms therein) .
  • the heterocycle may have from 1 to 4 ring heteroatoms independently selected from N, O, P, or S.
  • One or more N, C, or S atoms in a heterocycle may be oxidized.
  • a monocylic heterocycle may have 3 to 7 ring members (e.g., 2 to 6 carbon atoms and 1 to 3 heteroatoms independently selected from N, O, P, or S)
  • a bicyclic heterocycle may have 5 to 10 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms independently selected from N, O, P, or S)
  • the heterocycle that contains the heteroatom may be non-aromatic. Unless otherwise noted, the heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • the number of carbon atoms may be indicated by the prefix “C a -C b ” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent.
  • the “heterocycle” groups may be optionally substituted with one or more substitutions.
  • aryl generally refers to an aromatic substituent containing one ring or two or three fused rings.
  • the aryl substituent may have six to eighteen carbon atoms.
  • the aryl substituent may have six to fourteen carbon atoms.
  • the term “aryl” may refer to substituents such as phenyl, naphthyl and anthracenyl.
  • aryl may also contain substituents such as phenyl, naphthyl and anthracenyl that are fused to a C 4 -C 10 carbocyclic ring, such as a C 5 or a C 6 carbocyclic ring, or to a 4-to 10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group.
  • substituents such as phenyl, naphthyl and anthracenyl that are fused to a C 4 -C 10 carbocyclic ring, such as a C 5 or a C 6 carbocyclic ring, or to a 4-to 10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group.
  • the one or more substituents may be each bound to an aromatic carbon of the fused aryl group.
  • the fused C 4 -C 10 carbocyclic or 4-to 10-membered heterocyclic ring may optionally be optionally substituted.
  • aryl groups may include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl” ) , indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (also known as “phenalenyl” ) , and fluorenyl.
  • the number of carbon atoms may be indicated by the prefix “C a -C b ” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent.
  • the “aryl” groups may be optionally substituted with one or more substitutions.
  • heteroaryl generally refers to an aromatic ring structure containing from 5 to 14 ring atoms in which at least one of the ring atoms is a heteroatom (for example, oxygen, nitrogen, or sulfur) , with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • a heteroaryl may be a single ring or 2 or 3 fused rings.
  • heteroaryl substituents may include but not limited to: 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1, 2, 3-, 1, 2, 4-, 1, 2, 5-, or 1, 3, 4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1, 4-
  • the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
  • the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
  • the number of carbon atoms may be indicated by the prefix “C a -C b ” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent.
  • the “heteroaryl” groups may be optionally substituted with one or more substitutions.
  • halogen generally refers to fluorine (which may be depicted as -F) , chlorine (which may be depicted as -Cl) , bromine (which may be depicted as -Br) , or iodine (which may be depicted as -I) .
  • the halogen may be chlorine.
  • the halogen may be fluorine.
  • the halogen may be bromine.
  • cyano As used herein, the term “cyano” , either alone or within other terms, generally refers to formula -CN group.
  • nitro generally refers to formula -NO 2 group.
  • hydroxy generally refers to formula -OH group.
  • the “hydroxy” groups may be optionally substituted with one or more substitutions.
  • the term “phosphorous-containing group” generally refers to functional group containing on or more phosphorous atoms.
  • silicon-containing group generally refers to functional group containing on or more silicon atoms.
  • the silicon -containing group may refer to -SiH 3 .
  • the “silicon-containing group” may be optionally substituted with one or more substitutions.
  • thio As used herein, the term “thio” , either alone or within other terms, generally refers to formula -SH group.
  • the “thio” groups may be optionally substituted with one or more substitutions.
  • the “carboxyl” groups may be optionally substituted with one or more substitutions.
  • the “sulfonyl” groups may be optionally substituted with one or more substitutions.
  • the “sulfinyl” groups may be optionally substituted with one or more substitutions.
  • acyl generally refers to a carboxylic acid ester of the formula -C (O) R in which the non-carbonyl moiety of the ester group (i.e., R) may be selected from straight, branched, or cyclic alkyl.
  • the term acyl may include but not limited to acetyl, propionyl, butyryl and pentanoyl.
  • the number of carbon atoms may be indicated by the prefix “C a -C b ” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent.
  • the “acyl” groups may be optionally substituted with one or more substitutions.
  • thioacyl generally refers to the formula -C (S) R in which the moiety of the ester group (i.e., R) may be selected from straight, branched, or cyclic alkyl.
  • R the moiety of the ester group
  • the number of carbon atoms may be indicated by the prefix “C a -C b ” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent.
  • the “thioacyl” groups may be optionally substituted with one or more substitutions.
  • Ring generally refers to any covalently closed structure. Rings may include, for example, carbocycles, heterocycles, aryls and heteroaryls. Rings may be monocyclic or polycyclic. The “ring” groups may be optionally substituted with one or more substitutions.
  • the term “pharmaceutically acceptable salt” generally refers to a salt that may be pharmaceutically acceptable and that may possess the desired pharmacological activity of the parent compound.
  • Such salts may include: acid addition salts, formed with inorganic acids or formed with organic acids or basic addition salts formed with the conjugate bases of any of the inorganic acids wherein the conjugate bases comprise a cationic component.
  • aqueous or nonaqueous solutions generally refers to aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles may include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) , carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.
  • Injectable depot forms may be made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly (orthoesters) and poly (anhydrides) . Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release may be controlled. Depot injectable formulations may be also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers may include sugars such as lactose. Desirably, at least 95%by weight of the particles of the active ingredient may have an effective particle size in the range of 0.01 to 10 micrometers.
  • prodrug generally refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention.
  • Typical examples of prodrugs may include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs may include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, dedcylated, phosphorylated, dephosphorylated to produce the active compound.
  • cyclin-dependent kinase generally refers to a protein having an activity of regulating the cell cycle.
  • inhibiting cyclin-dependent kinase (CDK) activity may comprise interacting with a cyclin-CDK complex to block kinase activity.
  • CDK may comprise CDK7.
  • the UniPort ID for CDK7 may be P50613.
  • a substituent is “substitutable” or can be “substituted” if it comprises at least one atom that is bonded to one or more hydrogen atoms. If a substituent is described as being “substituted, ” hydrogen or a non-hydrogen substituent is in the place of a hydrogen substituent on a atom of the substituent.
  • a substituted alkyl substituent is an alkyl substituent wherein at least one hydrogen or a non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro substituent
  • difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each substituent may be identical or different (unless otherwise stated) .
  • each substituent may be selected independent of the other (s) .
  • Each substituent therefore may be identical to or different from the other substituent (s) .
  • optionally substituted or “optional substituent (s) ” generally refers to a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety.
  • R x is optionally substituted or R x is optionally substituted with R y ” may mean that R x may be substituted with 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 R y , for example, R x may be substituted with 0, 1, 2, 3, 4, or 5 R y , for example, R x may be substituted with 1, 2, or 3 R y , for example, R x may be substituted with one R y , for example, R x may be substituted with 2 R y , for example, R x may be substituted with 3 R y , for example, R x may be substituted with 4 R y , for example, R x may be substituted with 5 R y , for example, R x may be substituted with 6 R y , for example, R x may be substituted with 7 R y , for example, R x may be substituted with 8 R y , for example, R x may be substituted with 9 R y .
  • a non-hydrogen substituent may be any substituent that may be bound to an atom of the given moiety that is specified to be substituted.
  • substituent is itself optionally substituted by a further substituent.
  • the term “formula” may be hereinafter referred to as a “compound (s) of the invention” . Such terms are also defined to include all forms of the compound of formula, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof.
  • the compounds of formula, or pharmaceutically acceptable salts thereof may exist in unsolvated and solvated forms.
  • the complex When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity.
  • the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content may be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • the compounds of “formula” may have asymmetric carbon atoms.
  • the carbon-carbon bonds of the compounds of formula may be depicted herein using a solid line, a solid wedge, or a dotted wedge.
  • the use of a solid line to depict bonds to asymmetric carbon atoms may be meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc. ) at that carbon atom are included.
  • the use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms may be meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the present application may contain more than one asymmetric carbon atom.
  • a solid line to depict bonds to asymmetric carbon atoms may be meant to indicate that all possible stereoisomers are meant to be included.
  • the compounds of formula can exist as enantiomers and diastereomers or as racemates and mixtures thereof.
  • the use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of formula and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound may be meant to indicate that a mixture of diastereomers is present.
  • the compounds of the present application may exist as clathrates or other complexes. Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host may be present in stoichiometric or non-stoichiometric amounts. Also included may be complexes of formula containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized.
  • Stereoisomers of formula may include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of formula, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs) . Also included may be acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • the compounds of formula may exhibit the phenomena of tautomerism and structural isomerism.
  • the compounds of formula may exist in several tautomeric forms, including the enol and imine forms, and the keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms may be included within the scope of compounds of formula.
  • Tautomers may exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of formula.
  • the present invention also includes isotopically-labeled compounds, which are identical to those recited in formula above, but for the fact that one or more atoms may be replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that may be incorporated into compounds of formula include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • isotopically-labeled compounds of formula for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, may be useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes may be particularly used for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be used in some circumstances.
  • Isotopically-labeled compounds of formula may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.
  • the compounds of the present application may be used in the form of salts derived from inorganic or organic acids.
  • a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidity, or a desirable solubility in water or oil.
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
  • said R 1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.
  • said R 1 may be H (hydrogen) , F (fluorine) or Cl (chlorine) .
  • said R 1 may be H (hydrogen) , said R 1 may be F (fluorine) or said R 1 may be Cl (chlorine) .
  • said R 2 may be H.
  • said R 3 may be H.
  • said R 4 may be H.
  • said R 5 may be H.
  • said R 6 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted (C 1 -C 6 ) alkyl, and 3 to 12-ring-membered carbocycle.
  • R 6 may be optionally substituted (C 1 -C 6 ) alkyl or 3 to 12-ring-membered carbocycle.
  • R 6 may be optionally substituted ethyl, optionally substituted propyl or optionally substituted 5-ring-membered carbocycle.
  • R 6 may be optionally substituted ethyl, R 6 may be optionally substituted isopropyl or R 6 may be optionally substituted cyclopentanyl.
  • said R 7 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted (C 1 -C 6 ) acyl, optionally substituted (C 1 -C 6 ) alkyl, optionally substituted 3 to 12-ring-membered carbocycle, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7 may be optionally substituted (C 1 -C 6 ) acyl, optionally substituted (C 1 -C 6 ) alkyl, optionally substituted 3 to 12-ring-membered carbocycle, or optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7 may be optionally substituted formyl, optionally substituted methyl, optionally substituted propyl, optionally substituted cyclohexyl, optionally substituted piperidinyl or optionally substituted 1-azabicyclo [2.2.2] octane.
  • each said R 7-1 may be independently selected from optional substituents.
  • said R 7-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted 3 to 12-ring-membered carbocycle, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7-1 may be optionally substituted hydroxy, optionally substituted amino, optionally substituted 3 to 12-ring-membered carbocycle, or optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7-1 may be optionally substituted hydroxy, optionally substituted amino, optionally substituted cyclohexyl, or optionally substituted 6-ring-membered heterocycle.
  • said R 7- 1 may be optionally substituted hydroxy, optionally substituted amino, optionally substituted cyclohexyl, or optionally substituted piperidinyl.
  • said R 7 may be optionally substituted (C 1 -C 6 ) acyl, and said R 7-1 may be optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7 may be optionally substituted formyl, and said R 7-1 may be optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7 may be optionally substituted formyl, and said R 7-1 may be optionally substituted 6-ring-membered heterocycle.
  • said R 7 may be optionally substituted formyl, and said R 7-1 may be optionally substituted piperidinyl.
  • said R 7 may be optionally substituted (C 1 -C 6 ) alkyl, and said R 7-1 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted 3 to 12-ring-membered carbocycle, or optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7 may be optionally substituted methyl or optionally substituted propyl
  • said R 7-1 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted 3 to 12-ring-membered carbocycle, or optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7 may be optionally substituted methyl
  • said R 7-1 may be hydrogen, protium, deuterium, tritium, optionally substituted 3 to 12-ring-membered carbocycle, or optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7 may be optionally substituted methyl, and said R 7-1 may be hydrogen, protium, deuterium, tritium, optionally substituted cyclohexyl, or optionally substituted 6-ring-membered heterocycle.
  • said R 7 may be optionally substituted methyl, and said R 7-1 may be hydrogen, protium, deuterium, tritium, optionally substituted cyclohexyl, or optionally substituted piperidinyl.
  • said R 7 may be optionally substituted propyl, and said R 7-1 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, or optionally substituted amino.
  • said R 7 may be optionally substituted 3 to 12-ring-membered carbocycle, and said R 7-1 may be hydrogen, protium, deuterium, tritium, or optionally substituted hydroxy.
  • said R 7 may be optionally substituted cyclohexyl, and said R 7-1 may be hydrogen, protium, deuterium, tritium, or optionally substituted hydroxy.
  • said R 7 may be substituted with one or more R 7-1 , said R 7-1 may be substituted with one or more R 7-2 , each said R 7-2 may be independently selected from optional substituents.
  • said R 7-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, and optionally substituted amino.
  • said R 7-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, or optionally substituted amino.
  • said R 7 may be optionally substituted (C 1 -C 6 ) alkyl
  • said R 7-1 may be optionally substituted 3 to 12-ring-membered carbocycle, or optionally substituted 3 to 12-ring-membered heterocycle
  • said R 7-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, or optionally substituted amino.
  • said R 7 may be optionally substituted methyl
  • said R 7-1 may be optionally substituted cyclohexyl, or optionally substituted 6-ring-membered heterocycle
  • said R 7-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, or optionally substituted amino.
  • said R 7 may be optionally substituted methyl
  • said R 7-1 may be optionally substituted cyclohexyl
  • said R 7-2 may be hydrogen, protium, deuterium, tritium, or optionally substituted amino.
  • said R 7 may be optionally substituted methyl
  • said R 7-1 may be optionally substituted piperidinyl
  • said R 7-2 may be hydrogen, protium, deuterium, tritium, or optionally substituted hydroxy.
  • said R 8 may be hydrogen.
  • said R 7 and said R 8 combined with the atoms to which they are attached may form an optionally substituted ring B
  • said ring B may be optionally substituted 3 to 12-ring-membered heterocycle.
  • said ring B may be optionally substituted 5 to 6-ring-membered heterocycle.
  • said ring B may be optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted tetrahydropyrrolyl.
  • each said R B-1 may be independently selected from optional substituents.
  • said R B-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted (C 1 -C 6 ) acyl, optionally substituted (C 1 -C 6 ) alkyl, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R B-1 may be hydroxy, optionally substituted amino, optionally substituted formyl, optionally substituted methyl, or optionally substituted 6-ring-membered heterocycle.
  • said R B-1 may be hydroxy, optionally substituted amino, optionally substituted formyl, optionally substituted methyl, or optionally substituted piperidinyl.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted (C 1 -C 6 ) acyl, optionally substituted (C 1 -C 6 ) alkyl, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted formyl, optionally substituted methyl, and optionally substituted piperidinyl.
  • said ring B may be optionally substituted piperazinyl, and said R B-1 may be selected from the group consisting of hydrogen, protium, and deuterium.
  • said ring B may be optionally substituted tetrahydropyrrolyl, and said R B-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted (C 1 -C 6 ) alkyl.
  • said ring B may be optionally substituted tetrahydropyrrolyl, and said R B-1 may be hydrogen, protium, deuterium, tritium, optionally substituted amino, or optionally substituted methyl.
  • said ring B may be substituted with one or more R B-1 , said R B-1 may be substituted with one or more R B-2 , each said R B-2 may be independently selected from optional substituents.
  • said R B-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted (C 1 -C 6 ) alkyl, and optionally substituted 5 to 12-ring-membered heteroaryl.
  • said R B-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted methyl, optionally substituted ethyl, or optionally substituted 5-ring-membered heteroaryl.
  • said R B-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, optionally substituted methyl, optionally substituted ethyl, or optionally substituted pyrazolyl.
  • said ring B may be optionally substituted piperidinyl, said R B-1 may be optionally substituted amino, and said R B-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • said ring B may be optionally substituted piperidinyl, said R B-1 may be optionally substituted amino, and said R B-2 may be hydrogen, protium, deuterium, tritium, optionally substituted methyl, or optionally substituted ethyl.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be optionally substituted (C 1 -C 6 ) acyl
  • said R B-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted amino.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be optionally substituted formyl
  • said R B-2 may be hydrogen, protium, deuterium, tritium, or optionally substituted amino.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be optionally substituted (C 1 -C 6 ) alkyl
  • said R B-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, and optionally substituted 5 to 12-ring-membered heteroaryl.
  • said ring B may be optionally substituted piperidinyl, said R B-1 may be optionally substituted methyl, and said R B-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, or optionally substituted 5 to 12-ring-membered heteroaryl.
  • said ring B may be optionally substituted piperidinyl, said R B-1 may be optionally substituted methyl, and said R B-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted amino, or optionally substituted pyrazolyl.
  • said ring B may be optionally substituted tetrahydropyrrolyl
  • said R B-1 may be optionally substituted (C 1 -C 6 ) alkyl
  • said R B-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted amino.
  • said ring B may be optionally substituted tetrahydropyrrolyl
  • said R B- 1 may be optionally substituted methyl
  • said R B-2 may be hydrogen, protium, deuterium, tritium, or optionally substituted amino.
  • said ring B may be substituted with one or more R B-1 , said R B-1 may be substituted with one or more R B-2 , said R B-2 may be substituted with one or more R B-3 , each said R B-3 may be independently selected from optional substituents.
  • said R B-3 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted (C 1 -C 6 ) alkyl.
  • said R B-3 may be hydrogen, protium, deuterium, tritium, optionally substituted amino, or optionally substituted methyl.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be optionally substituted (C 1 -C 6 ) acyl
  • said R B-2 may be optionally substituted amino
  • said R B-3 may be hydrogen, protium, deuterium, tritium, or optionally substituted (C 1 -C 6 ) alkyl.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be optionally substituted formyl
  • said R B-2 may be optionally substituted amino
  • said R B-3 may be hydrogen, protium, deuterium, tritium, or optionally substituted (C 1 -C 6 ) alkyl.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be optionally substituted formyl
  • said R B-2 may be optionally substituted amino
  • said R B-3 may be hydrogen, protium, deuterium, tritium, or optionally substituted methyl.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be optionally substituted (C 1 -C 6 ) alkyl
  • said R B-2 may be optionally substituted amino or optionally substituted 3 to 12-ring-membered heterocycle
  • said R B-3 may be hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted (C 1 -C 6 ) alkyl.
  • said ring B may be optionally substituted piperidinyl
  • said R B- 1 may be optionally substituted methyl
  • said R B-2 may be optionally substituted amino or optionally substituted pyrazolyl
  • said R B-3 may be hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted (C 1 -C 6 ) alkyl.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be optionally substituted methyl
  • said R B-2 may be optionally substituted amino
  • said R B-3 may be hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • said ring B may be optionally substituted piperidinyl
  • said R B- 1 may be optionally substituted methyl
  • said R B-2 may be optionally substituted amino
  • said R B-3 may be hydrogen, protium, deuterium, tritium, and optionally substituted methyl.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be optionally substituted methyl
  • said R B-2 may be optionally substituted pyrazolyl
  • said R B-3 may be hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted (C 1 -C 6 ) alkyl.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be optionally substituted methyl
  • said R B-2 may be optionally substituted pyrazolyl
  • said R B-3 may be hydrogen, protium, deuterium, tritium, optionally substituted amino, and optionally substituted methyl.
  • said ring B may be substituted with one or more R B-1 , said R B-1 may be substituted with one or more R B-2 , said R B-2 may be substituted with one or more R B-3 , said R B-3 may be substituted with one or more R B-4 , each said R B-4 may be independently selected from optional substituents.
  • said R B-4 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.
  • said R B-4 may be F.
  • said ring B may be optionally substituted piperidinyl, said R B-1 may be optionally substituted methyl, said R B-2 may be optionally substituted pyrazolyl, said R B-3 may be methyl, and said R B-4 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.
  • said ring B may be optionally substituted piperidinyl, said R B-1 may be optionally substituted methyl, said R B-2 may be optionally substituted pyrazolyl, said R B-3 may be methyl, and said R B-4 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and F.
  • said ring A may be optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A may be optionally substituted pyrazolyl.
  • each said R A-1 may be independently selected from optional substituents.
  • said R A-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted (C 1 -C 6 ) acyl, optionally substituted (C 1 -C 6 ) alkyl, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R A-1 may be hydrogen, protium, deuterium, tritium, optionally substituted formyl, optionally substituted methyl, optionally substituted propyl, or optionally substituted 6-ring-membered heterocycle.
  • said R A-1 may be hydrogen, protium, deuterium, tritium, optionally substituted formyl, optionally substituted methyl, optionally substituted isopropyl, or optionally substituted piperazinyl.
  • said ring A may be optionally substituted pyrazolyl, and said R A-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted (C 1 -C 6 ) acyl, optionally substituted (C 1 -C 6 ) alkyl, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said ring A may be optionally substituted pyrazolyl, and said R A-1 may be hydrogen, protium, deuterium, tritium, optionally substituted formyl, optionally substituted methyl, optionally substituted isopropyl, or optionally substituted piperazinyl.
  • said ring A may be substituted with one or more R A-1 , said R A-1 may be substituted with one or more R A-2 , each said R A-2 may be independently selected from optional substituents.
  • said R A-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted (C 1 -C 6 ) alkyl, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R A-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted propyl, or optionally substituted 6-ring-membered heterocycle.
  • said R A-2 may be hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, optionally substituted isopropyl, or optionally substituted piperazinyl.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted (C 1 -C 6 ) acyl
  • said R A-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted formyl
  • said R A-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said ring A may be optionally substituted pyrazolyl, said R A-1 may be optionally substituted formyl, and said R A-2 may be hydrogen, protium, deuterium, tritium, or optionally substituted 6-ring-membered heterocycle.
  • said ring A may be optionally substituted pyrazolyl, said R A-1 may be optionally substituted formyl, and said R A-2 may be hydrogen, protium, deuterium, tritium, or optionally substituted piperazinyl.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted (C 1 -C 6 ) alkyl
  • said R A-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted methyl, or optionally substituted isopropyl
  • said R A-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.
  • said ring A may be optionally substituted pyrazolyl, said R A-1 may be optionally substituted 3 to 12-ring-membered heterocycle, and said R A-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • said ring A may be optionally substituted pyrazolyl, said R A-1 may be optionally substituted piperazinyl, and said R A-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted piperazinyl
  • said R A-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted isopropyl.
  • said ring A may be substituted with one or more R A-1 , said R A-1 may be substituted with one or more R A-2 , said R A-2 may be substituted with one or more R A-3 , each said R A-3 may be independently selected from optional substituents.
  • said R A-3 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • said R A-3 may be hydrogen, protium, deuterium, tritium, optionally substituted methyl or optionally substituted ethyl.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted (C 1 -C 6 ) acyl
  • said R A-2 may be optionally substituted 3 to 12-ring-membered heterocycle
  • said R A-3 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • said ring A may be optionally substituted pyrazolyl, said R A-1 may be optionally substituted formyl, said R A-2 may be optionally substituted piperazinyl, and said R A-3 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • said ring A may be optionally substituted pyrazolyl, said R A-1 may be optionally substituted formyl, said R A-2 may be optionally substituted piperazinyl, and said R A-3 may be hydrogen, protium, deuterium, tritium, optionally substituted methyl or optionally substituted ethyl.
  • said ring A may be substituted with one or more R A-1 , said R A-1 may be substituted with one or more R A-2 , said R A-2 may be substituted with one or more R A-3 , said R A-3 may be substituted with one or more R A-4 , each said R A-4 may be independently selected from optional substituents.
  • said R A-4 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted (C 1 -C 6 ) acyl
  • said R A-2 may be optionally substituted 3 to 12-ring-membered heterocycle
  • said R A-3 may be optionally substituted (C 1 -C 6 ) alkyl
  • R A-4 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted formyl
  • said R A-2 may be optionally substituted piperazinyl
  • said R A-3 may be optionally substituted ethyl
  • R A-4 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.
  • the present application provides a compound having the structure of formula (I-A) ,
  • said R 1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.
  • said R 1 may be H (hydrogen) , F (fluorine) or Cl (chlorine) .
  • said R 1 may be H (hydrogen) , said R 1 may be F (fluorine) or said R 1 may be Cl (chlorine) .
  • R 2 may be H.
  • R 3 may be H.
  • R 4 may be H.
  • R 5 may be H.
  • R 6 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • R 6 may be optionally substituted propyl.
  • R 6 may be optionally substituted isopropyl.
  • said R 7 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 7 may be optionally substituted 6-ring-membered heterocycle.
  • said R 7 may be optionally substituted piperidinyl.
  • said R 8 may be H.
  • said R 7 and said R 8 combined with the atoms to which they are attached may form an optionally substituted ring B.
  • said ring B is optionally substituted 3 to 12-ring-membered heterocycle.
  • said ring B is optionally substituted 6-ring-membered heterocycle.
  • said ring B is optionally substituted piperidinyl.
  • said ring B may be substituted with one or more R B-1 , each said R B-1 may be independently optional substituent.
  • said R B-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, and optionally substituted amino.
  • said ring B may be optionally substituted 3 to 12-ring-membered heterocycle, and said R B-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, and optionally substituted amino.
  • said ring B may be optionally substituted piperidinyl, and said R B-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, optionally substituted hydroxy, and optionally substituted amino.
  • said ring A may be optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A may be optionally substituted pyrazolyl.
  • said ring A may be substituted with one or more R A-1 , each said R A-1 may be independently selected from optional substituents.
  • said R A-1 may be optionally substituted (C 1 -C 6 ) alkyl.
  • said R A- 1 may be optionally substituted methyl or optionally substituted propyl.
  • said R A-1 may be optionally substituted methyl or optionally substituted isopropyl.
  • said ring A may be optionally substituted pyrazolyl, and said R A-1 may be optionally substituted (C 1 -C 6 ) alkyl.
  • said ring A may be optionally substituted pyrazolyl, and said R A-1 may be optionally substituted methyl or optionally substituted isopropyl.
  • said ring A may be substituted with one or more R A-1 , said R A-1 may be substituted with one or more R A-2 , each said R A-2 may be independently selected from optional substituents.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted (C 1 -C 6 ) alkyl
  • said ring A may be optionally substituted pyrazolyl, said R A-1 may be optionally substituted isopropyl, and said R A-2 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.
  • said ring A may be substituted with one or more R A-1 , said R A-1 may be substituted with one or more R A-2 , said R A-2 may be substituted with one or more R A-3 , each said R A-3 may be independently selected from optional substituents.
  • said R A-3 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • said R A-3 may be hydrogen, protium, deuterium, tritium, optionally substituted methyl or optionally substituted ethyl.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted (C 1 -C 6 ) alkyl
  • said R A-2 may be optionally substituted piperazinyl
  • said R A-3 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted methyl
  • said R A-2 may be optionally substituted piperazinyl
  • said R A-3 may be hydrogen, protium, deuterium, tritium, optionally substituted methyl or optionally substituted ethyl.
  • said ring A may be substituted with one or more R A-1 , said R A-1 may be substituted with one or more R A-2 , said R A-2 may be substituted with one or more R A-3 , said R A-3 may be substituted with one or more R A-4 , each said R A-4 may be independently selected from optional substituents.
  • said R A-4 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted (C 1 -C 6 ) alkyl
  • said R A-2 may be optionally substituted piperazinyl
  • said R A-3 may be optionally substituted (C 1 -C 6 ) alkyl
  • said R A-4 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.
  • said ring A may be optionally substituted pyrazolyl
  • said R A-1 may be optionally substituted methyl
  • said R A-2 may be optionally substituted piperazinyl
  • said R A-3 may be optionally substituted ethyl
  • said R A-4 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted hydroxy.
  • the present application provides a compound having the structure of formula (I-B) ,
  • R 1 may be H (hydrogen) .
  • R 2 may be H.
  • R 3 may be H.
  • R 4 may be H.
  • R 5 may be H.
  • said R 6 may be optionally substituted (C 1 -C 6 ) alkyl.
  • said R 6 may be optionally substituted propyl.
  • said R 6 may be optionally substituted isopropyl.
  • said R 7 and said R 8 combined with the atoms to which they are attached may form an optionally substituted ring B.
  • said ring B may be optionally substituted 3 to 12-ring-membered heterocycle.
  • said ring B may be optionally substituted 6-ring-membered heterocycle.
  • said ring B may be optionally substituted piperidinyl.
  • said ring B may be substituted with one or more R B-1 , each said R B-1 may be independently optional substituent.
  • said R B-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted amino.
  • said ring B may be optionally substituted piperidinyl
  • said R B-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted amino.
  • said ring A may be optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A may be optionally substituted pyrazolyl.
  • said R A-1 may be optionally substituted 3 to 12-ring-membered heterocycle.
  • said R A-1 may be optionally substituted 6-ring-membered heterocycle.
  • said R A-1 may be optionally substituted 6-ring-membered heterocycle containing two N.
  • said R A-1 may be optionally substituted piperazinyl.
  • said R A-1 may be substituted with one or more R A-2 , each said R A-2 may be independently optional substituent.
  • said R A-2 may be optionally substituted (C 1 -C 6 ) alkyl.
  • said R A-2 may be optionally substituted propyl.
  • said R A-2 may be optionally substituted isopropyl.
  • said R A-1 may be optionally substituted piperazinyl, and said R A-2 may be optionally substituted isopropyl.
  • the present application provides a compound having the structure of formula (I-C) ,
  • R 1 may be H (hydrogen) .
  • R 2 may be H.
  • R 3 may be H.
  • R 4 may be H.
  • R 5 may be H.
  • said R 6 may be optionally substituted (C 1 -C 6 ) alkyl.
  • said R 6 may be optionally substituted propyl.
  • said R 6 may be optionally substituted isopropyl.
  • said ring B may be optionally substituted piperidinyl or optionally substituted tetrahydropyrrolyl.
  • R B-2 may be H.
  • said n may be 2.
  • said ring A may be optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A may be optionally substituted pyrazolyl.
  • the present application provides a compound having the structure of formula (I-D) ,
  • R 1 may be H (hydrogen) .
  • R 2 may be H.
  • R 3 may be H.
  • R 4 may be H.
  • R 5 may be H.
  • said R 6 may be optionally substituted (C 1 -C 6 ) alkyl.
  • said R 6 may be optionally substituted propyl.
  • said R 6 may be optionally substituted isopropyl.
  • said ring B may be optionally substituted piperidinyl.
  • R B-2 may be optionally substituted methyl.
  • said ring A may be optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A may be optionally substituted pyrazolyl.
  • the present application provides a compound having the structure of formula (I-E) ,
  • R 1 may be H (hydrogen) .
  • R 2 may be H.
  • R 3 may be H.
  • R 4 may be H.
  • R 5 may be H.
  • said R 6 may be optionally substituted (C 1 -C 6 ) alkyl.
  • said R 6 may be optionally substituted propyl.
  • said R 6 may be optionally substituted isopropyl.
  • said ring B may be optionally substituted piperidinyl.
  • R B-2 may be optionally substituted ethyl.
  • said n may be 2.
  • said ring A may be optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A may be optionally substituted pyrazolyl.
  • the present application provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound may be selected from the group consisting of:
  • the present application provides a compound having the structure of formula (II) ,
  • said R 1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and halogen.
  • said R 1 may be H (hydrogen) , F (fluorine) or Cl (chlorine) .
  • said R 1 may be H (hydrogen) .
  • R 2 may be H.
  • R 3 may be H.
  • R 4 may be H.
  • R 5 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted (C 1 -C 6 ) alkyl.
  • R 5 may be optionally substituted propyl.
  • R 5 may be optionally substituted isopropyl.
  • said R 6 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted 3 to 12-ring-membered heterocycle.
  • said R 6 may be optionally substituted 6-ring-membered heterocycle.
  • said R 6 may be optionally substituted piperidinyl.
  • said R 7 may be H.
  • said R 6 and said R 7 combined with the atoms to which they are attached may form an optionally substituted ring B.
  • said ring B is optionally substituted 3 to 12-ring-membered heterocycle.
  • said ring B is optionally substituted 6-ring-membered heterocycle.
  • said ring B is optionally substituted piperidinyl.
  • said ring B may be substituted with one or more R B-1 , each said R B-1 may be independently optional substituent.
  • said R B-1 may be selected from the group consisting of hydrogen, protium, deuterium, tritium, and optionally substituted amino.
  • said ring A may be optionally substituted 5 to 12-ring-membered heteroaryl.
  • said ring A may be optionally substituted 5-ring-membered heteroaryl.
  • said ring A may be optionally substituted 5-ring-membered heteroaryl containing two N.
  • said ring A may be optionally substituted pyrazolyl.
  • the present application provides a compound or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, wherein, said compound may be selected from the group consisting of:
  • the present application provides a method for inhibiting cyclin-dependent kinase (CDK) activity, said method comprising administering to a subject in need thereof an effective amount of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing.
  • said cyclin-dependent kinase (CDK) may be CDK 7.
  • said method may be selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.
  • the present application provides use the compound of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing of the present application in the preparation of a drug and/or a kit for use in inhibiting cyclin-dependent kinase (CDK) activity.
  • said cyclin-dependent kinase (CDK) may be CDK 7.
  • said method of using said drug and/or said kit may be selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.
  • the present application provides the compound of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing of the present application for use in inhibiting cyclin-dependent kinase (CDK) activity.
  • said cyclin-dependent kinase (CDK) may be CDK 7.
  • said method or said use may be selected from the group consisting of an in vitro method, an ex vivo method, and an in vivo method.
  • the present application provides a composition comprising a compound of the present application, or a pharmaceutically acceptable salt, prodrug, or metabolite thereof, or a solvate or hydrate of any of the foregoing, and optionally a pharmaceutically acceptable carrier.
  • the compounds of the application may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • the compounds of the present application may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration may include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration may include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • the compounds of the present application may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In some cases, the compounds of the present application may also be administered intranasally or by inhalation. In some cases, the compounds of the present application may be administered rectally or vaginally. In another embodiment, the compounds of the present application may also be administered directly to the eye or ear.
  • the dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. Dosage levels of body weight per day may be useful.
  • Suitable subjects according to the present invention include mammalian subjects. Mammals according to the present invention may include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
  • the present application provides use of one or more compounds of the present application for the preparation of a medicament.
  • the compounds of the present application may be administered as compound per se.
  • pharmaceutically acceptable salts may be suitable for medical applications because of their greater aqueous solubility relative to the parent compound.
  • compositions may comprise a compound of the present application presented with a pharmaceutically acceptable carrier.
  • the carrier may be a solid product, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which may contain the active compounds.
  • a compound of the present application may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances may also be present.
  • the compounds of the present invention may be administered by any suitable route, maybe in the form of a pharmaceutical composition adapted to such a route.
  • the active compounds and compositions may be administered orally, rectally, parenterally, or topically.
  • the compounds of the present application may be used, alone or in combination with other therapeutic agents.
  • the compound (s) of the present application and other therapeutic agent (s) may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially.
  • the administration of two or more compounds “in combination” may mean that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other.
  • the two or more compounds may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration.
  • Standard abbreviations may be used, e.g., bp, base pair (s) ; kb, kilobase (s) ; pl, picoliter (s) ; s or sec, second (s) ; min, minute (s) ; h or hr, hour (s) ; aa, amino acid (s) ; nt, nucleotide (s) ; i.m., intramuscular (ly) ; i.p., intraperitoneal (ly) ; s.c., subcutaneous (ly) ; and the like.
  • 2, 6-dichloro-9-isopropyl-9H-purine 2, 6-dichloro-9H-purine (10.0g, 52.91mmol) , isopropyl bromide (32.5g, 264.55mmol) , potassium carbonate (21.9g, 158.73mmol) and dimethyl sulfoxide (50ml) were added to a 250 ml two-necked flask, and the mixture was stirred at room temperature for 96hours.
  • the reaction solution was added dropwise to water, ethyl acetate was added for extraction three times, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 9.8 g of light yellow solid.
  • 2, 6-dichloro-9-isopropyl-9H-purine 2, 6-dichloro-9H-purine (10.0g, 52.91mmol) , isopropyl bromide (32.5g, 264.55mmol) , potassium carbonate (21.9g, 158.73mmol) and dimethyl sulfoxide (50ml) were added to a 250 ml two-necked flask, and the mixture was stirred at room temperature for 96hours.
  • the reaction solution was added dropwise to water, ethyl acetate was added for extraction three times, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 9.8 g of light yellow solid.
  • tert-butyl 4- ( (6- ( (2- (1H-pyrazol-1-yl) benzyl) amino) -9-isopropyl-9H-purin-2-yl) amino) methyl) -4-hydroxypiperidine-1-carboxylate: To a solution of N- (2- (1H-pyrazol-1-yl) benzyl) -2-chloro-9-isopropyl-9H-purin-6-amine (200 mg, 543.72 ⁇ mol) in DMSO (2 mL) was added tert-butyl 4- (aminomethyl) -4-hydroxypiperidine-1-carboxylate (187.83 mg, 815.58 ⁇ mol) and potassium carbonate (150.30 mg, 1.09 mmol) , the mixture was stirred at 165°C for 10hrs.
  • 2, 6-dichloro-9-isopropyl-9H-purine 2, 6-dichloro-9H-purine (10.0g, 52.91mmol) , isopropyl bromide (32.5g, 264.55mmol) , potassium carbonate (21.9g, 158.73mmol) and dimethyl sulfoxide (50ml) were added to a 250 ml two-necked flask, and the mixture was stirred at room temperature for 96hours.
  • the reaction solution was added dropwise to water, ethyl acetate was added for extraction three times, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 9.8 g of light yellow solid.
  • reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined.
  • the organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo to obtain 138mg oil.
  • Crude purified by silica gel column (Methanol/dichloromethane 0-10%) to obtain 88mg oil.
  • 2, 6-dichloro-9-isopropyl-9H-purine 2, 6-dichloro-9H-purine (10.0g, 52.91mmol) , isopropyl bromide (32.5g, 264.55mmol) , potassium carbonate (21.9g, 158.73mmol) and dimethyl sulfoxide (50ml) were added to a 250 ml two-necked flask, and the mixture was stirred at room temperature for 96hours.
  • the reaction solution was added dropwise to water, ethyl acetate was added for extraction three times, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 9.8 g of light yellow solid.
  • reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined.
  • the organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo to obtain 138mg oil.
  • Crude purified by silica gel column (Methanol/dichloromethane 0-10%) to obtain 88mg oil.
  • the oil was dissolved in water and added ethyl acetate to extracted the impurities.
  • 2, 6-dichloro-9-isopropyl-9H-purine 2, 6-dichloro-9H-purine (10.0g, 52.91mmol) , isopropyl bromide (32.5g, 264.55mmol) , potassium carbonate (21.9g, 158.73mmol) and dimethyl sulfoxide (50ml) were added to a 250 ml two-necked flask, and the mixture was stirred at room temperature for 96hours.
  • the reaction solution was added dropwise to water, ethyl acetate was added for extraction three times, the organic phases were combined, washed twice with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 9.8 g of light yellow solid.
  • reaction solution was added dropwise to water, extracted twice with ethyl acetate, and the organic phases were combined.
  • the organic phase was washed twice with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo to obtain 82mg oil.
  • Crude purified by silica gel column (10%ammonia methanol solution: DCM 0%to 20%) to obtain 41mg off-white soild.

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Abstract

L'invention concerne des composés en tant qu'inhibiteurs puissants de kinases cycline-dépendantes (CDK), ou des sels pharmaceutiquement acceptables de ceux-ci. L'invention concerne également des compositions correspondantes.
PCT/CN2022/111324 2021-08-11 2022-08-10 Inhibiteur de kinases cycline-dépendantes WO2023016477A1 (fr)

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US18/682,476 US20240352016A1 (en) 2021-08-11 2022-08-10 A cyclin-dependent kinase inhibitor
CN202280055252.7A CN117916235A (zh) 2021-08-11 2022-08-10 周期蛋白依赖性激酶抑制剂
JP2024508806A JP2024534028A (ja) 2021-08-11 2022-08-10 サイクリン依存性キナーゼ阻害剤
EP22855458.0A EP4380930A4 (fr) 2021-08-11 2022-08-10 Inhibiteur de kinases cycline-dépendantes

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WO2023186065A1 (fr) * 2022-04-02 2023-10-05 Taizhou Eoc Pharma Co., Ltd. Inhibiteur de kinase dependante de la cycline

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CN117916235A (zh) 2024-04-19
US20240352016A1 (en) 2024-10-24
EP4380930A1 (fr) 2024-06-12
TW202320787A (zh) 2023-06-01
WO2023016477A9 (fr) 2024-04-25
JP2024534028A (ja) 2024-09-18
EP4380930A4 (fr) 2025-01-01

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